This revised Beeson Patient-Oriented Research Career Development Award (K23) project will provide the mentorship, didactic coursework and individualized instruction to develop Richard D. King, MD, PhD, into a leader in geriatric research. This will build upon his graduate work in computational neuroscience, and his expertise in the disorders of the aging brain derived from his residency and fellowship training in neurology. Dr. King's training goals include 1) building expertise in technical and computational aspects of neuroimaging analysis software development, 2) gaining proficiency with methods of cognitive neuroscience in the geriatric population, 3) learning how to manage complex epidemiologic factors common in elderly patients, and 4) developing proficiency with translating novel imaging analysis tools into clinical practice. Through the training program and research plan outlined in this application, Dr. King will acquire the broad expertise and knowledge base needed to become and independent physician-scientist with a focus on cognitive disorder of elderly subjects. The proposed research is to develop a new structural imaging analysis technique based upon a quantitative metric known as fractal dimension (f3D). There are several novel aspects to this approach. First, f3D is perfectly suited to detect shape changes that occur with atrophy of the human cerebral cortex. Secondly, f3D is a quantitative measure of shape which provides a more robust evaluation than the current standard of qualitative subjective assessments (i.e. "mild" or "moderate" atrophy). Thirdly, f3D integrates information over a range of spatial scales. Dr. King has written software to compute f3D using 3D models of the cortex extracted from high-contrast magnetic resonance (MR) images. It is essential to understand the extent and distribution of size and shape changes occurring with healthy aging because many of these changes are not associated with cognitive dysfunction. With the guidance of mentors expert in cognitive aging, computer science and statistics, Dr. King will create a normative statistical imaging atlas of healthy brain aging using MR images of healthy subjects from two databases. The age-weighted normative atlas will then be used to statistically quantify the effects of neurodegenerative disease on cortical f3D values using MR images of subjects with mild cognitive impairment and mild Alzheimer's disease. Finally, to understand how this imaging approach may be used in clinical practice, it is important to move beyond studies that use highly-selected clinical populations. Dr. King will perform the cortical f3D analysis using prospective imaging data from patients with cognitive complaints seeking clinical evaluation. The data will enable a prospective trial on the role of cortical f3D in clinical practice. PUBLIC HEALTH RELEVANCE: This project will establish a firm foundation for leadership in aging research through mentorship, didactic coursework and individualized training. The focus of the proposed research is to further refine and begin validation of global and regional fractal measures of cortical complexity as a novel method to assess brain aging and the earliest changes of Alzheimer's disease. The clinically relevant quantitative methods developed in this study may improve the sensitivity and specificity for distinguishing normal aging from early neurodegenerative disease on an individual basis.